Leading edge competition promotes context-dependent responses to receptor inputs to resolve directional dilemmas in neutrophil migration.

Maintaining persistent migration in complex environments is critical for neutrophils to reach infection sites. Neutrophils avoid getting trapped, even when obstacles split their front into multiple leading edges. How they re-establish polarity to move productively while incorporating receptor inputs under such conditions remains unclear.

Directional reorientation of migrating neutrophils is limited by suppression of receptor input signaling at the cell rear through myosin II activity.

To migrate efficiently to target locations, cells must integrate receptor inputs while maintaining polarity: a distinct front that leads and a rear that follows. Here we investigate what is necessary to overwrite pre-existing front-rear polarity in neutrophil-like HL60 cells migrating inside straight microfluidic channels. Using subcellular optogenetic receptor activation, we show that receptor inputs can reorient weakly polarized cells, but the rear of strongly polarized cells is refractory to new inputs.

Neutrophil-like HL-60 cells expressing only GFP-tagged β-actin exhibit nearly normal motility.

Observations of actin dynamics in living cells using fluorescence microscopy have been foundational in the exploration of the mechanisms underlying cell migration. We used CRISPR/Cas9 gene editing to generate neutrophil-like HL-60 cell lines expressing GFP-β-actin from the endogenous locus (ACTB). In light of many previous reports outlining functional deficiencies of labeled actin, we anticipated that HL-60 cells would only tolerate a monoallelic edit, as biallelic edited cells would produce no normal β-actin.

Efficient Front-Rear Coupling in Neutrophil Chemotaxis by Dynamic Myosin II Localization.

Efficient chemotaxis requires rapid coordination between different parts of the cell in response to changing directional cues. Here, we investigate the mechanism of front-rear coordination in chemotactic neutrophils. We find that changes in the protrusion rate at the cell front are instantaneously coupled to changes in retraction at the cell rear, while myosin II accumulation at the rear exhibits a reproducible 9-15-s lag.

Analytical and numerical study of diffusion-controlled drug release from composite spherical matrices.

We investigate, both analytically and numerically, diffusion-controlled drug release from composite spherical formulations consisting of an inner core and an outer shell of different drug diffusion coefficients. Theoretically derived analytical results are based on the exact solution of Fick's second law of diffusion for a composite sphere, while numerical data are obtained using Monte Carlo simulations. In both cases, and for the range of matrix parameter values considered in this work, fractional drug release profiles are described accurately by a stretched exponential function.

Quantifying diffusion-controlled drug release from spherical devices using Monte Carlo simulations.

We numerically calculate drug release profiles from simple spherical devices using Monte Carlo simulations, when diffusion is the dominant release mechanism. Release curves are accurately described by the stretched exponential function, also known as the Weibull function. The dependence of the two stretched exponential parameters on the size of the spherical device and the drug diffusion coefficient is investigated and simple analytical relations are provided.